The present invention relates to pyrimidine nucleoside compounds and their use to treat viral infections of Varicella Zoster Virus, Epstein Barr Virus and Kaposi""s Sarcoma virus, also known as HV-8 and related complications of these viral infections. In another aspect of the present invention, the use of one or more nucleoside compound to increase the rentention or the metabolic/catabolic half-life of 5-fluorouracil (FU) in cancer patients is also described.
As human bacterial infections have become more manageable and treatable through the use of increasingly available antibiotic agents, viral infections have remained a more difficult and less treatable target. Emphasis in finding agents to treat viral infections has remained a high priority. Problematic virus is Varicella zoster virus, Epstein Barr virus and Kaposi""s Sarcoma virus.
Varicella zoster virus (VZV), a member of the herpes virus family, is a main causative agent for a primary infection (varicella and chickenpox) as well as a recurrent disease (zoster and shingles). Snoeck, et al., xe2x80x9cChemotherapy of varicella-zoster virus-infections.xe2x80x9d Intl. J. Antimicrob. Agents 1994, 4, 211-226. The course of varicella is generally benign in immunocompetent patients, however, in immunocompromised patients, particularly patients suffering from the acquired immune deficiency syndrome (AIDS), transplant recipients, and cancer patients, VZV infections can be life-threatening. Snoeck, et al. xe2x80x9cCurrent pharmacological approaches to the therapy of varicella zoster virus infections. A guide to treatment.xe2x80x9d, Drugs 1999, 57, 187-206; and Lee, P. J. and Annunziato, P. xe2x80x9cCurrent management of herpes zoster.xe2x80x9d Infections in Medicine 1998, 15, 709-713.
The current treatment for patients infected with VZV and for immunocompetent patients at risk, such as pregnant women or premature infants, is based on acyclovir (ACV). See, Whitley, R. J. xe2x80x9cTherapeutic approaches to varicella-zoster virus infections.xe2x80x9d J. Infect. Dis. 1992, 166, Suppl. 1: 51-57; Shepp, et al. xe2x80x9cTreatment of varicella-zoster virus in severely immunocompromised patients: a randomized comparison of acyclovir and vidarabine.xe2x80x9d New Engl. J. Med. 1986, 314, 208-212; Whitley, et al. xe2x80x9cDisseminated herpes zoster in the immunocompromised host: a comparative trial of acyclovir and vidarabine.xe2x80x9d J. Infect. Dis. 1992, 165, 450-455. However, the efficacy and low oral bioavailability of ACV (De Miranda and Blum, xe2x80x9cPharmacokinetics of acyclovir after intravenous and oral administration.xe2x80x9d J. Antimicrob. Chemother. 1983, 12, Suppl. B: 29-37), as well as the emergence of drug-resistant virus strains (See, Pahwa, et al. xe2x80x9cContinuous varicella-zoster infection associated with acyclovir resistance in a child with AIDSxe2x80x9d J. Am. Med. Assoc. 1988, 260, 2879-2882; Linnemann, et al. xe2x80x9cEmergence of acyclovir-resistant varicella zoster virus in an AIDS patient on prolonged acyclovir therapy.xe2x80x9d AIDS 1990, 4, 577-579; Jacobson, et al. xe2x80x9cAcyclovir-resistant varicella zoster virus infection afetr chronic acyclovir therapy in patients with the acquired immunodeficiency syndrome (AIDS).xe2x80x9d Ann. Intern. Med. 1990, 112, 187-191), have stimulated the development of new compounds for the treatment of VZV infection.
Among the efforts to develop new compounds, (E)-5-(2-bromovinyl)uracil (BVU) analogues, such as (E)-5-(2-bromovinyl)-2xe2x80x2-deoxyuridine (BVDU) and 1-xcex2-D-arabinofuranosyl-(E)-5-(2-bromovinyl)uracil (BVaraU), have been found to exhibit potent anti-VZV activity. See, for example, De Clercq, et al. xe2x80x9c(E)-5-(2-Bromovinyl)-2xe2x80x2-deoxyuridine: a potent and selective anti-herpes agent.xe2x80x9d Proc. Natl. Acad. Sci. USA 1979, 76, 2947-2951 and Machida, et al., xe2x80x9cAntiherpes-viral and anticellular effects of 1-xcex2-D-arabinofuranosyl-E-5-(2-halogenovinyl)uracils. Antimicrob. Agents Chemother. 1981, 20, 47-52. However, metabolic stability of BVDU by pyrimidine nucleoside phosphorylase and, recently, drug interaction of BVaraU with anticancer agent 5-FU, which resulted in death of several patients with cancer and herpes zoster, have been potential drawbacks and limit their use. Desgranges, et al., Biochem. Pharmacol. 1983, 32, 3583; David, S., xe2x80x9cDeaths bring clinical trials under scrutiny in Japan.xe2x80x9d Nature 1994, 369, 697 and Watabe, et al., xe2x80x9cLethal drug interactions of the new antiviral, sorivudine, with anticancer prodrugs of 5-fluorouracil.xe2x80x9d Yakugaku Zasshi 1997, 117, 910-921. Efforts to address these problems have led to several interesting nucleosides, such as 4xe2x80x2-thio-BVDU and the carbocyclic analog carba BvdU. Dyson, et al. xe2x80x9cThe synthesis and antiviral activity of some 4xe2x80x2-thio-2xe2x80x2-deoxy nucleoside anlogues.xe2x80x9d J. Med. Chem. 1991, 34, 2782-2786 and Herdewijn, et al., xe2x80x9cSynthesis and antiviral activity of the carbocyclic analogues of (E)-5-(2-halovinyl)-2xe2x80x2-deoxyuridines and (E)-5-(2-halovinyl)-2xe2x80x2-deoxycytidines.xe2x80x9d J. Med. Chem. 1985, 28, 550-555. However, the carba derivatives perform very poorly in vivo although they are resistant to degradation and in cell cultures have antiviral activities comparable to those of the parent compounds. Spadari, et al., xe2x80x9c5-Iodo-2xe2x80x2-deoxy-L-uridine and (E)-5-(2-bromovinyl)-2xe2x80x2-deoxy-L-uridine: selective phosphorylation by herpes simplex virus type 1 thymidine kinase, antiherpetic activity, and cytotoxicity studies.xe2x80x9d Mol. Pharmacol. 1995, 47, 1231-1238.
L-xcex2-BVOddU was originally discovered by Krzystof, et al. to have inhibitory activity against HSV-1 replication. Although this compound is known, the potential usage for the treatment of VZV has not been reported. See Krzystof, et al., Bioorganic and Medical Chemistry Letter. Vol 4 (22):2667-2672.
Epstein-Barr virus (EBV) is an important human pathogen, related to herpes simplex virus (HSV). Elliot Kieff, Virology, Third Edition, Edited by B. N. Fields, D. M. Knipe, P. M. Howley, et al. Epstein-Barr Virus and Its Replication. Chapter 74. Pp 2343-2396 and Alan B. Rickinson and Elliot Kieff, Ibid. Chapter 75, pp. 2397-2446. EBV is a lymphotrophic member of the genus Lumphocryptovirus, and belongs to the sub-family gammaherpesvirinae. Another new member of human virus also belonging to this family is Kaposi""s sarcoma-associated herpes virus (KSHV/HHV8). Chang, et al., Science, 266:1865-1869 (1994); Cesarman, et al., N. Eng. J. Med., 332:1186-1191 (1995); Soulier, et al., Blood, 86:1276-1280 (1995). There are two sub-types of EBV identified and their genomes are nearly identical, but there is no clear relationship between EBV associated diseases and EBV sub-types. Abdul-Hamid, et al., Virology, 190: 168-175 (1992) and Sample, et al., J. Virol., 64:4084-4092 (1990). The lytic EBV genome is a linear, double-stranded, 172 Kbp DNA composed of 60 mol % guanine and cytosine. The genome has been sequenced and it was found to be capable of encoding a number of virus specified proteins, which include several enzymes involved in virus DNA synthesis during lytic infection of EBV. In vitro, EBV infection is generally limited to B-lymphocytes, although epithelial cells can also be infected. Sixbey, et al., Nature, 306:480-483 (1983). In humans, the virus genome can be detected in B-lymphocytes and T-lymphocytes as well as epithelial cells. The EBV genome replicates lytically in the linear form and can also be latent as supercoiled circular DNA. The expression of the EBV genome in lytic infected cells is very different from latent infected cells. EBV specified DNA plymerase, Dnase and dThd kinase are only expressed in cells upon lytic DNA replication. Cell culture studies indicated the essential role of EBV specified DNA polymerase for EBV DNA replication during lytic infection, but not for the maintenance of supercoiled EBV DNA in latent infected cells. A unique set of EBV proteins including EBVNA 1 and sometimes, EBNA LP, 2, 3A, 3B, 3C, LMP 1 as well as LMP2 is expressed in latent infected or transformed cells. Elliot Kieff, Virology, Third Edition, Edited by B. N. Fields, D. M. Knipe, P. M. Howley, et al. Epstein-Barr Virus and Its Replication. Chapter 74. Pp 2343-2396 and Alan B. Rickinson and Elliot Kieff, Ibid. Chapter 75, pp. H2397-2446.
Structurally, EBV is similar to that of other herpes viruses- it has a double-stranded DNA genome contained within a nucleocapsid, which is surrounded by a lipid envelope containing viral glycoproteins. A tegument protein occupies the space between the envelope and the nucleocapsid.
While primary EBV infection in infancy appears to be almost asymptomatic, a proportion (in some studies up to 50%) of serologically confirmed primary infections in adolescence or early adult life are manifested as infectious mononucleosis (IM) also called the xe2x80x9cKissing Diseasexe2x80x9d. Transmission of EBV is primarily through the saliva, although some infections are transmitted via blood transfusions. A high percentage ( greater than 85%) of patients in the acute phase of infectious mononucleosis secrete EBV. In the mid-1970""s, EBV was identified to cause fatal IM/X-linked lymphoproliferative syndrome (XLP) in young male children who had X-linked immunodeficiency. Sullivan and Wood, (Immunodeficiency Rev., 1:325-347 (1989). Fatal EBV infection is also found to be associated with nonfamilial monophagocytic syndrome (VAHS) for which there is no effective therapy. Alan B. Rickinson and Elliot Kieff, Virology, Third Edition, Edited by B. N. Fields, D. M. Knipe, P. M. Howley, et al. Epstein-Barr Virus and Its Replication, Chapter 75, pp. 2397-2446 and Craig, et al., Am. J. Clin. Path., 97:189-194 (1992).
Epstein-Barr virus is also recognized as a causative agent of B-cell proliferative diseases, and is linked to a variety of disease states, including a rare progressive mononucleosis-like syndrome and oral hair leukoplakia in AIDS patients. EBV has also been associated with certain types of cancer such as Burkitt""s lymphoma, nasopharyngeal carcinoma, Hodgkin""s disease, EBV-associated T-cell lymphoma and nasal T-cell lymphoma. Certain patients, in particular, those with suppressed immune systems such as AIDS patients and organ transplant patients who are being treated with immunosuppressive agents, are particularly susceptible to EBV manifestations, especially the development of EBV-associated lymphomas.
Chu, et al., in PCT application PCT/US95/01253, describe a number of L-nucleoside analogs for use in the treatment of Hepatitis B virus and Epstein-Barr virus infections. One agent disclosed in the PCT application, 2xe2x80x2-fluoro-5-methyl-xcex2-L-arabinofuranosyluridine (L-FMAU), showed good activity against EBV. Noteworthy is the fact that when a 5-methyl group of L-FMAU was substituted with a bromo group, the anti-EBV activity decreased.
Several compounds have been shown to have activity against EBV replication in culture at concentrations non-toxic to cell growth. These include acyclovir (ACV), gancyclovir (DHPG), pencyclovir, D-FMAU and its analogs, 5-bromovinyl dUrd, phosphonoformate and phosphorothioate oligonucleotides. See Lin, et al., Antimicrob. Agents and Chemo. (February) 32(2):265-267 (1988); Lin, et al., Antimicrob. Agents and Chemo., 32(7):1068-1072 (1988); Cheng, et al., Proc. Natl. Acad. Sci. USA, 80:2767-2770(1983); Datta, et al., Proc. Natl., Acad. Sci. USA, 77:5163-5166 (1980); Datta, et al., Virology, 114:52-59 (1981); Lin, et al., Antimicrob. Agents and Chemo., 31:1431-1433 (1987); Olka and Calendar, Virology, 104:219-223 (1980); Lin, et al., J. Virol., 50:50-55 (1984); Yao, et al., Antimicrob. Agents and Chemo., 37:1420-1425 (1993) and Yao, et al., Biochem. Pharm., (51):941-947(1966).
PCT application PCT/US97/20647 (WO 98/20879) describes the use of a number of 5-substituted xcex2-L-OddU analogues for the treatment of EBV, VZV and HV-8. The 5-Bromo and 5-Iodo compounds disclosed as being the most active in the series of compounds presented.
It is an object of the present invention to provide compounds, pharmaceutical compositions and methods of treating and/or preventing infections from Epstein Barr virus (EBV), Varicella-Zoster virus (VZV) and Kaposi""s Sarcoma Virus (HV-8) and related conditions and/or disease states in patients.
It is an additional object of the present invention to provide, in certain embodiments a method of increasing the retention or metabolic/catabolic half-life of 5-Fluorouracil in cancer patients.